Lack of phosphoinositide 3-kinase-γ attenuates ventilator-induced lung injury*

Lionetti, Vincenzo; Lisi, A; Patrucco, Enrico; Giuli, Paolo De; Milazzo, Maria Giovanna; Ceci, S.; Wymann, Matthias P.; Lena, A; Gremigni, Vittorio; Fanelli, Vito; Hirsch, Emilio; Ranieri, V. Marco

doi:10.1097/01.ccm.0000190909.70601.2c

Cited by 41 publications

(28 citation statements)

References 46 publications

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“…PI3K has recently been implicated in VILI coupled with surfactant depletion and ischemia in studies by Lionetti et al (30). They first injured the lungs of wild-type, PI3K␥ knockout, and PI3K␥ kinase dead mice by repeated saline lavage, excised the lungs, and ventilated the lungs without perfusion with static low pressure inflation or ventilation with high (40 ml/kg) or low (7 ml/kg) tidal volumes for 3 h. In lungs of PI3K␥ null mice, histological indexes of lung injury and phosphorylation of Akt and ERK1/2 were reduced compared with wild type, but indexes of apoptosis were increased.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, lungs in our preparations were continuously perfused, and we measured K f , a specific measure of vascular permeability. Lionetti et al (30) concluded that suppression of downstream Akt activation in PI3KϪ/Ϫ mice protected against VILI by increased apoptosis and favoring apoptosis over necrosis of lung cells. However, we observed no increase in apoptosis in our preparations during 2 h of ventilation without additional insults.…”

Section: Discussionmentioning

confidence: 99%

“…PI3Ks play an important role in cytoskeletal remodeling, metabolic control, and proinflammatory cytokine production (68). Lionetti et al (30) found reduced histological evidence of lung injury after high volume ventilation in PI3K␥ knockout mice after lung injury with saline lavage and 3 h of ischemia. Also, Uhlig et al (67) showed that PI3K inhibition attenuated NF-B activation and inflammatory cytokine gene activation during high PIP ventilation.…”

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confidence: 99%

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Phosphoinositide 3-kinase, Src, and Akt modulate acute ventilation-induced vascular permeability increases in mouse lungs

Miyahara¹,

Hamanaka²,

Weber³

et al. 2007

American Journal of Physiology-Lung Cellular and Molecular Phys

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To determine the role of phosphoinositide 3-OH kinase (PI3K) pathways in the acute vascular permeability increase associated with ventilator-induced lung injury, we ventilated isolated perfused lungs and intact C57BL/6 mice with low and high peak inflation pressures (PIP). In isolated lungs, filtration coefficients ( Kf) increased significantly after ventilation at 30 cmH2O (high PIP) for successive periods of 15, 30 (4.1-fold), and 50 (5.4-fold) min. Pretreatment with 50 μM of the PI3K inhibitor, LY-294002, or 20 μM PP2, a Src kinase inhibitor, significantly attenuated the increase in Kf, whereas 10 μM Akt inhibitor IV significantly augmented the increased Kf. There were no significant differences in Kf or lung wet-to-dry weight (W/D) ratios between groups ventilated with 9 cmH2O PIP (low PIP), with or without inhibitor treatment. Total lung β-catenin was unchanged in any low PIP isolated lung group, but Akt inhibition during high PIP ventilation significantly decreased total β-catenin by 86%. Ventilation of intact mice with 55 cmH2O PIP for up to 60 min also increased lung vascular permeability, indicated by increases in lung lavage albumin concentration and lung W/D ratios. In these lungs, tyrosine phosphorylation of β-catenin and serine/threonine phosphorylation of Akt, glycogen synthase kinase 3β (GSK3β), and ERK1/2 increased significantly with peak effects at 60 min. Thus mechanical stress activation of PI3K and Src may increase lung vascular permeability through tyrosine phosphorylation, but simultaneous activation of the PI3K-Akt-GSK3β pathway tends to limit this permeability response, possibly by preserving cellular β-catenin.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Phosphoinositide 3-kinase, Src, and Akt modulate acute ventilation-induced vascular permeability increases in mouse lungs

Miyahara¹,

Hamanaka²,

Weber³

et al. 2007

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…(9). Of note, various reports have now identified augmented injury in animal models of both VILI and lipopolysaccharide-induced ALI associated with Akt inhibition (10,11) and we previously reported increased agonist-induced barrier disruption in Akt1-silenced EC monolayers (9). These findings suggest that Akt depletion contributes directly to the elaboration of acute inflammatory lung injury via increased lung vascular permeability.…”

Section: What This Study Adds To the Fieldmentioning

confidence: 71%

Role of Growth Arrest and DNA Damage–inducible α in Akt Phosphorylation and Ubiquitination after Mechanical Stress-induced Vascular Injury

Mitra

Sammani

Wang

et al. 2011

Am J Respir Crit Care Med

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Rationale: The stress-induced growth arrest and DNA damageinducible a (GADD45a) gene is up-regulated by mechanical stress with GADD45a knockout (GADD45a 2/2 ) mice demonstrating both increased susceptibility to ventilator-induced lung injury (VILI) and reduced levels of the cell survival and vascular permeability signaling effector (Akt). However, the functional role of GADD45a in the pathogenesis of VILI is unknown. Objectives: We sought to define the role of GADD45a in the regulation of Akt activation induced by mechanical stress. Methods: VILI-challenged GADD45a 2/2 mice were administered a constitutively active Akt1 vector and injury was assessed by bronchoalveolar lavage cell counts and protein levels. Human pulmonary artery endothelial cells (EC) were exposed to 18% cyclic stretch (CS) under conditions of GADD45a silencing and used for immunoprecipitation, Western blotting or immunofluoresence. EC were also transfected with mutant ubiquitin vectors to characterize site-specific Akt ubiquitination. DNA methylation was measured using methylspecific polymerase chain reaction assay. Measurements and Main Results: Studies exploring the linkage of GADD45a with mechanical stress and Akt regulation revealed VILIchallenged GADD45a 2/2 mice to have significantly reduced lung injury on overexpression of Akt1 transgene. Increased mechanical stress with 18% CS in EC induced Akt phosphorylation via E3 ligase tumor necrosis factor receptor-associated factor 6 (TRAF6)-mediated Akt K63 ubiquitination resulting in Akt trafficking and activation at the membrane. GADD45a is essential to this process because GADD45a-silenced endothelial cells and GADD45a 2/2 mice exhibited increased Akt K48 ubiquitination leading to proteasomal degradation. These events involve loss of ubiquitin carboxyl terminal hydrolase 1 (UCHL1), a deubiquitinating enzyme that normally removes K48 polyubiquitin chains bound to Akt thus promoting Akt K63 ubiquitination. Loss of GADD45a significantly reduces UCHL1 expression via UCHL1 promoter methylation resulting in increased Akt K48 ubiquitination and reduced Akt levels. Conclusions: These studies highlight a novel role for GADD45a in the regulation of site-specific Akt ubiquitination and activation and implicate a significant functional role for GADD45a in the clinical predisposition to VILI.Keywords: GADD45a; AKT; UCHL1; ubiquitin; mechanical stress Acute lung injury (ALI) is a devastating disorder commonly encountered in the intensive care unit, with approximately 75,000 deaths annually in the United States (1). Although insults, such as infection and trauma, often precipitate in ALI, ALI morbidity and mortality are heavily influenced by excessive mechanical stress produced by mechanical ventilation. Mechanical ventilator support is required to provide adequate gas exchange but potentially generates excessive mechanical stress, a condition known as ventilator-induced lung injury (VILI) (2). Multiple lines of evidence, including marked ethnic and racial disparities in ALI mortality, support the contribu...

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“…High PIP-induced lung vascular permeability increases were attenuated by blockade of PI3K or Src family kinases (SFK), but augmented by blockade of Akt (320). Lionetti et al (277) observed attenuation of VILI in PI3K knockout mice compared to wild-type mice. PI3K knockout mice had more apoptotic cells but less phosphorylation of Akt and ERK1/2, although there were no differences in cytokine production between knockout and wildtype mice.…”

Section: Free Radicals In Ventilator-induced Lung Injurymentioning

confidence: 97%

Acute Lung Injury and Pulmonary Vascular Permeability: Use of Transgenic Models

Parker

2011

Comprehensive Physiology

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Acute lung injury is a general term that describes injurious conditions that can range from mild interstitial edema to massive inflammatory tissue destruction. This review will cover theoretical considerations and quantitative and semi-quantitative methods for assessing edema formation and increased vascular permeability during lung injury. Pulmonary edema can be quantitated directly using gravimetric methods, or indirectly by descriptive microscopy, quantitative morphometric microscopy, altered lung mechanics, high-resolution computed tomography, magnetic resonance imaging, positron emission tomography, or x-ray films. Lung vascular permeability to fluid can be evaluated by measuring the filtration coefficient (Kf) and permeability to solutes evaluated from their blood to lung clearances. Albumin clearances can then be used to calculate specific permeability-surface area products (PS) and reflection coefficients (σ). These methods as applied to a wide variety of transgenic mice subjected to acute lung injury by hyperoxic exposure, sepsis, ischemia-reperfusion, acid aspiration, oleic acid infusion, repeated lung lavage, and bleomycin are reviewed. These commonly used animal models simulate features of the acute respiratory distress syndrome, and the preparation of genetically modified mice and their use for defining specific pathways in these disease models are outlined. Although the initiating events differ widely, many of the subsequent inflammatory processes causing lung injury and increased vascular permeability are surprisingly similar for many etiologies.

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Lack of phosphoinositide 3-kinase-γ attenuates ventilator-induced lung injury*

Abstract: Silencing PI3Kgamma seems to attenuate functional and morphological consequences of ventilator-induced lung injury independently of inhibitory effects on cytokines release but through the enhancement of pulmonary apoptosis.

Cited by 41 publications

References 46 publications

Phosphoinositide 3-kinase, Src, and Akt modulate acute ventilation-induced vascular permeability increases in mouse lungs

Phosphoinositide 3-kinase, Src, and Akt modulate acute ventilation-induced vascular permeability increases in mouse lungs

Role of Growth Arrest and DNA Damage–inducible α in Akt Phosphorylation and Ubiquitination after Mechanical Stress-induced Vascular Injury

Acute Lung Injury and Pulmonary Vascular Permeability: Use of Transgenic Models

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